There is continued interest in the pharmacological activity of apomorphine and its analogs. Apomorphine is of clinical benefit in relieving the tremor resulting from Parkinsonism. Furthermore, it has been suggested as an adjunct to L-dopa therapy where the latter fails to manage tremor. The clinical use of apomorphine is confounded by its poor chemical stability, unsatisfactory oral absorption, its short duration of action and its toxicity. The severe, reversible dose-dependent extrarenal azotemia occurring in patients treated with apomorphine is particularly troublesome. A program embracing organic synthesis, analytical chemistry, biopharmaceutics and pharmacology-toxicology is proposed for the preparation of potentially useful and less toxic apomorphine-like drugs. A study of apomorphine-induced azotemia in animals will be undertaken. It is proposed that an animal model be established that responds in a like manner to man. Apomorphine and its congeners will be tested in the uremia model. Analogs will be pharmacologically evaluated via unilateral turning in rats electrothermally lesioned in the left nigrostriatal pathway and in mice possessing (drug induced) supersensitive CNS dopamine receptors. Promising drug candidates will be tested for their effects on brain catecholamine biosynthesis in mice. Work will continue on the synthesis, stability, and metabolism of apomorphine prodrugs. Some analogs already prepared, appear to be orally active and have an extended duration of action. Metabolic correlates of pharmacological activity and toxicity (especially azotemia) will be sought. Throughout these investigations, analytical methods will be developed for the determination of apomorphine, its analogs and metabolites in biological fluids. Preliminary results with gas chromatography and radiochemical procedures indicate that methods can be developed that are applicable to human investigations. BIBLIOGRAPHIC REFERENCES: S.C. Gad, S.W. Leslie, R.G. Brown, and R.V. Smith, "Inhibitory Effects of Dithiothreitol and Sodium Bisulfite on Isolated Rat Ileum and Atrium," Life Sci., 20, 657 (1977). D.M. Baaske, J.E. Keiser, and R.V. Smith, "Gas Chromatographic Determination of Apomorphine in Plasma," J. Chromatogr., in press (1977).